Heterocyclic compounds for the treatment of disease

Abstract

Described herein are heterocyclic compounds, compositions, and methods for their use for the treatment of disease.

1 . A compound having the Formula (I), or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         X 1  is N; X 2 , X 3 , and X 4  are each CR 1 ; or 
         X 2  is N; X 1 , X 3 , and X 4  are each CR 1 ; or 
         X 3  is N; X 1 , X 2 , and X 4  are each CR 1 ; or 
         X 4  is N; X 1 , X 2 , and X 3  are each CR 1 ; 
       
       
         
           
           
               
               
           
         
          is selected from 
       
       
         
           
           
               
               
           
         
         Z is —O—, —S—, —N(R 4 )—, —CH 2 —, —OCH 2 —, or —CH 2 O—; 
         each R 1  is independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted —(C 1 -C 2 alkylene)—(C 3 -C 8 cycloalkyl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted —(C 1 -C 2 alkylene)—(C 2 -C 9 heterocycloalkyl), optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl), —CF 3 , —OR 10 , —SR 10 , —N(R 11 )R 12 , —N(R 11 )S(O) 2 R 15 ; —N(R 13 )N(R 11 )R 12 , —N(R 13 )N(R 11 )S(O) 2 R 15 , —C(O)R 14 , —C(O)OR 10 , —C(S)OR 10 , —C(O)SR 10 , —C(O)N(R 11 )R 12 , —C(S)N(R 11 )R 12 , —C(O)N(R 11 )S(O) 2 R 15 , —C(S)N(R 11 )S(O) 2 R 15 , —C(O)N(R 13 )N(R 11 )R 12 , —C(S)N(R 13 )N(R 11 )R 12 , and —C(O)N(R 13 )N(R 11 )S(O) 2 R 15 ; 
         each R 2  is independently selected from the group consisting of halogen, optionally substituted C 1 -C 6 alkyl, —OR 20 , —SR 20 , —N(R 21 )R 22 , —C(O)R 20 , —C(O)N(R 21 )R 22 , and —N(R 23 )C(O)R 20 ; 
         R 3  is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); 
         R 4  is hydrogen or optionally substituted C 1 -C 6 alkyl, 
         R 10 , R 13  and R 14  are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); 
         R 11  and R 12  are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); or optionally R 11  and R 12  together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring; 
         R 15  is selected from the group consisting of optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8  cycloalkyl, optionally substituted aryl optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); 
         R 20  and R 23  are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); 
         R 21  and R 22  are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); 
         or optionally R 21  and R 22  together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring; 
         n is 0-4; and 
         p is 0 or 1. 
       
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein X 1  is N; X 2 , X 3 , and X 4  are each CR 1 . 
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein X 2  is N; X 1 , X 3 , and X 4  are each CR 1 . 
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein X 3  is N; X 1 , X 2 , and X 4  are each CR 1 . 
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein X 4  is N; X 1 , X 2 , and X 3  are each CR 1 . 
     
     
         7 . (canceled) 
     
     
         8 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 1  is independently selected from the group consisting of hydrogen, halogen, and —CF 3 . 
     
     
         9 . (canceled) 
     
     
         10 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 2  is independently selected from the group consisting of halogen and optionally substituted C 1 -C 6 alkyl. 
     
     
         11 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3  is selected from the group consisting of hydrogen and optionally substituted C 1 -C 6 alkyl. 
     
     
         12 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein is N 
       
         
           
           
               
               
           
         
       
     
     
         13 .- 17 . (canceled) 
     
     
         18 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein Z is —O—, —OCH 2 —, or —CH 2 O—. 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. 
     
     
         23 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of  claim 1 ; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         27 . A method of modulating sphingosine-1-phosphate (S1P) receptor activity comprising contacting the S1P receptor, or portion thereof, with a compound, or a pharmaceutically acceptable salt, or solvate thereof, according to  claim 1 . 
     
     
         28 . A method of treating a disease, disorder or condition in a mammal that would benefit from sphingosine-1-phosphate (S1P) receptor modulation comprising administering to the mammal a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, or solvate thereof, according to  claim 1 . 
     
     
         29 . The method of  claim 28 , wherein the disease, disorder or condition in a mammal is selected from multiple sclerosis, ulcerative colitis, and Crohn's disease. 
     
     
         30 . A compound having the Formula (II), or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         X 1 , X 2 , X 3 , and X 4  are each CR 1 ; or 
         X 1  is N; X 2 , X 3 , and X 4  are each CR 1 ; or 
         X 2  is N; X 1 , X 3 , and X 4  are each CR 1 ; or 
         X 3  is N; X 1 , X 2 , and X 4  are each CR 1 ; or 
         X 4  is N; X 1 , X 2 , and X 3  are each CR 1 ; 
       
       
         
           
           
               
               
           
         
          is selected from 
       
       
         
           
           
               
               
           
         
         Z is —O—, —S—, —N(R 4 )—, —CH 2 —, —OCH 2 —, or —CH 2 O—; 
         each R 1  is independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted —(C 1 -C 2 alkylene)—(C 3 -C 8 cycloalkyl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted —(C 1 -C 2 alkylene)—(C 2 -C 9 heterocycloalkyl), optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl), —CF 3 , —OR 10 , —SR 10 , —N(R 11 )R 12 , —N(R 11 )S(O) 2 R 15 ; —N(R 13 )N(R 11 )R 12 , —N(R 13 )N(R 11 )S(O) 2 R 15 , —C(O)R 14 , —C(O)OR 10 , —C(S)OR 10 , —C(O)SR 10 , —C(O)N(R 11 )R 12 , —C(S)N(R 11 )R 12 , —C(O)N(R 11 )S(O) 2 R 15 , —C(S)N(R 11 )S(O) 2 R 15 , —C(O)N(R 13 )N(R 11 )R 12 , —C(S)N(R 13 )N(R 11 )R 12 , and —C(O)N(R 13 )N(R 11 )S(O) 2 R 15 ; 
         each R 2  is independently selected from the group consisting of halogen, optionally substituted C 1 -C 6 alkyl, —OR 20 , —SR 20 , —N(R 21 )R 22 , —C(O)R 20 , —C(O)N(R 21 )R 22 , and —N(R 23 )C(O)R 20 ; 
         R 3  is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); 
         R 4  is hydrogen or optionally substituted C 1 -C 6 alkyl, 
         R 10 , R 13  and R 14  are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); 
         R 11  and R 12  are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); or optionally R 11  and R 12  together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring; 
         R 15  is selected from the group consisting of optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8  cycloalkyl, optionally substituted aryl optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); 
         R 20  and R 23  are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); 
         R 21  and R 22  are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted —(C 1 -C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted —(C 1 -C 2 alkylene)-(heteroaryl); or optionally R 21  and R 22  together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring; 
         n is 0-4; and 
         p is 0 or 1.